Dynamic interactions of neurons and glia in the ventral midbrain mediate reward and addiction behavior. We studied gene expression in 212,713 ventral midbrain single nuclei from 95 individuals with history of opioid misuse, and individuals without drug exposure. Chronic exposure to opioids was not associated with change in proportions of glial and neuronal subtypes, however glial transcriptomes were broadly altered, involving 9.5 − 6.2% of expressed genes within microglia, oligodendrocytes, and astrocytes. Genes associated with activation of the immune response including interferon, NFkB signaling, and cell motility pathways were upregulated, contrasting with down-regulated expression of synaptic signaling and plasticity genes in ventral midbrain non-dopaminergic neurons. Ventral midbrain transcriptomic reprogramming in the context of chronic opioid exposure included 325 genes that previous genome-wide studies had linked to risk of substance use traits in the broader population, thereby pointing to heritable risk architectures in the genomic organization of the brain’s reward circuitry.

腹侧中脑神经元和神经胶质细胞的动态相互作用介导奖励和成瘾行为。我们研究了 95 个有阿片类药物滥用史的个体和没有药物暴露史的个体的 212,713 个腹侧中脑单核的基因表达。长期接触阿片类药物与神经胶质细胞和神经元亚型比例的变化无关，但神经胶质细胞转录组发生了广泛改变，涉及小胶质细胞、少突胶质细胞和星形胶质细胞内9.5%~6.2%的表达基因。与免疫反应激活相关的基因（包括干扰素、NFkB信号传导和细胞运动途径）上调，而腹侧中脑非多巴胺能神经元中突触信号传导和可塑性基因的表达下调。长期阿片类药物暴露背景下的腹侧中脑转录组重编程包括 325 个基因，之前的全基因组研究已将这些基因与更广泛人群中物质使用特征的风险联系起来，从而指出大脑奖励回路的基因组组织中的可遗传风险结构。